Brain Stimulation As a Therapy for Epilepsy

  • Jeffrey H. Goodman
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 548)


The failure of current antiepileptic therapies to adequately treat a significant number of epileptic patients highlights the need for the development of new treatments for the disorder. A new strategy that is currently being developed is to deliver electrical stimulation directly to the brain to decrease or prevent seizure activity. Clinical evidence that electrical stimulation could interfere with seizure activity was initially reported in the 1930’s. However, many of these early studies consisted of case reports or were poorly controlled. In addition, there were a number of studies that failed to observe any beneficial effect of brain stimulation on seizures. More recently, deep brain stimulation has been used successfully to treat patients with movement disorders and vagus nerve stimulation has been shown to effectively decrease seizure activity in a select population of epilepsy patients. These advances have led to a reexamination of the potential therapeutic benefits of deep brain stimulation for the treatment of epilepsy. There is now experimental and clinical evidence that direct electrical stimulation of the brain can prevent or decrease seizure activity. However, several fundamental questions remain to be resolved. They include where in the brain the stimulus should be delivered and what type of stimulation would be most effective. One goal of this research is to combine the beneficial aspects of electrical stimulation with seizure detection technology in an implantable responsive stimulator. The device will detect the onset of a seizure and deliver an electrical stimulus that will safely block seizure activity without interfering with normal brain function.


Substantia Nigra Deep Brain Stimulation Brain Stimulation Superior Colliculus Seizure Activity 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Litt B, Esteller J, Eschauz M et al. Epileptic seizures may begin hours in advance of clinical onset: a report of five patients. Neuron 2001; 30: 51–64.PubMedCrossRefGoogle Scholar
  2. 2.
    Walker AE. An oscillographic study of the cerebello-cerebral relationship. J Neurophysiol 1938; 1: 16–23.Google Scholar
  3. 3.
    Cooper IS, Amin I, Gilman S. The effect of chronic cerebellar stimulation upon epilepsy in man Trans Am Neurol Assoc 1973; 98: 192–196.Google Scholar
  4. 4.
    Cooper IS, Upton AR. Effects of cerebellar stimulation on epilepsy, the EEG and cerebral palsy in man Electroencephalogr Clin Neurophysiol 1978; S34: 349–354.Google Scholar
  5. 5.
    Myers RR, Burchiel KJ, Stockard JJ et al. Effects of acute and chronic paleocerebellar stimulation on experimental models of epilepsy in the cat: studies with enflurane, pentylenetetrazol, penicillin and chlorolose. Epilepsia 1975; 16: 257–267.PubMedCrossRefGoogle Scholar
  6. 6.
    Lockard JS, Ojemann GA, Condon WC et al. Cerebellar stimulation in alumina-gel monkey model: inverse relationship between clinical seizures and EEG interictal bursts. Epilepsia 1979; 20: 223–234.PubMedCrossRefGoogle Scholar
  7. 7.
    Wright GD, McLellan DL, Brice JG. A double-blind trial of chronic cerebellar stimulation in twelve patients with severe epilepsy. J Neurol Neurosurg Psychiatry 1984; 47: 769–774.PubMedCrossRefGoogle Scholar
  8. 8.
    Fisher RS, Uematsu S, Krauss GL et al. Placebo-controlled pilot study of thalamic stimulation in treatment of intractable seizure Epilepsia 1992; 33: 841–851.Google Scholar
  9. 9.
    The Vagus Nerve Stimulation Group. A randomized controlled trial of chronic vagus nerve stimulation for treatment of medically-intractable seizures. Neurology 1995; 45: 224–230.CrossRefGoogle Scholar
  10. 10.
    Schmidt D. Vagus nerve stimulation for the treatment of epilepsy. Epilepsy and Behavior 2001; 2: S1 - S5.CrossRefGoogle Scholar
  11. 11.
    Hodaie M, Wennberg RA, Dostrovsky JO et al. Chronic anterior thalamus stimulation for intractable epilepsy. Epilepsia 2002; 43: 603–608.PubMedCrossRefGoogle Scholar
  12. 12.
    Benabid AL, Minotti L, Koudsie A et al. Antiepileptic effect of high-frequency stimulation of the subthalamic nucleus (Corpus Luysi) in a case of medically intractable epilepsy caused by focal dysplasia: a 30-month follow-up: Technical Case Report. Neurosurgery 2002; 50: 1385–1392.PubMedGoogle Scholar
  13. 13.
    Velasco M, Velasco F, Velasco AL et al. Subacute electrical stimulation of the hippocampus blocks intractable temporal lobe seizures and paroxysmal EEG activities. Epilepsia 2000; 41: 158–169.PubMedCrossRefGoogle Scholar
  14. 14.
    Litt B, Baltuch G. Brain stimulation for epilepsy. Epilepsy and Behavior 2001; 2: S61 - S67.CrossRefGoogle Scholar
  15. 15.
    Litt B, Lehnertz K. Seizure prediction and the preseizure period. Curr Opin Neurol 2002; 15: 173–177.PubMedCrossRefGoogle Scholar
  16. 16.
    Krout KE, Lowewy AD. Parabrachial nucleus projections to midline and intralaminar thalamic nuclei of the rat. J Comp Neurol 2000; 428: 475–494.PubMedCrossRefGoogle Scholar
  17. 17.
    Magdaleno-Madrigal VM, Valdez-Cruz A, Martinez-Vargas D et al. Effect of electrical stimulation of the nucleus of the solitary tract on the development of electrical amygdaloid kindling in the cat. Epilepsia 2002; 43: 964–969.PubMedCrossRefGoogle Scholar
  18. 18.
    Krahl SE, Clark KB, Smith DC et al. Locus coeruleus lesions suppress the seizure-attenuating effects of vagus nerve stimulation. Epilepsia 1998; 39: 709–714.PubMedCrossRefGoogle Scholar
  19. 19.
    Gale K. Subcortical structures and pathways involved in convulsive seizure generation. J Clin Neurophysiol 1992; 9: 264–277.PubMedCrossRefGoogle Scholar
  20. 20.
    Deransart C, Riban V, Le-Pham BT et al. Evidence for the involvement of the pallidum in the modulation of seizures in a genetic model of absence epilepsy in the rat. Neurosci Lett 1999; 265: 131–134.PubMedCrossRefGoogle Scholar
  21. 21.
    Maiti A, Snider R. Cerebellar control of basal forebrain seizures: amygdala and hippocampus. Epilepsia 1975; 6: 521–533.CrossRefGoogle Scholar
  22. 22.
    Hablitz JJ, Rea G. Cerebellar nuclear stimulation in generalized penicillin epilepsy. Brain Res Bull 1976; 1: 599–601.PubMedCrossRefGoogle Scholar
  23. 23.
    Mirski MA, Rossell LA, Terry JB et al. Anticonvulsant effect of anterior thalamic high frequency electrical stimulation in the rat. Epilepsy Res 1997; 28: 89–100.PubMedCrossRefGoogle Scholar
  24. 24.
    Vercueil L, Benazzouz A, Deransart C et al. High-frequency stimulation of the subthalamic nucleus suppresses absence seizures in the rat: comparison with neurotoxic lesions. Epilepsy Res 1998; 31: 39–46.PubMedCrossRefGoogle Scholar
  25. 25.
    Mirski M, Fisher R. Electrical stimulation of the mammillary nuclei increases seizure threshold to pentylenetetrazol in rats. Epilepsia 1994; 35: 1309–1316.PubMedCrossRefGoogle Scholar
  26. 26.
    Neuman RS. Suppression of penicillin-induced focal epileptiform activity by locus ceruleus stimulation: mediation by an alpha-l-adrenoreceptor. Epilepsia 1986; 27: 359–366.PubMedCrossRefGoogle Scholar
  27. 27.
    Ferraro G, Sardo P, Sabatino M et al. Locus coeruleus noradrenaline system and focal penicillin hippocampal epilepsy: neurophysiological study. Epilepsy Res 1994; 19: 215–220.PubMedCrossRefGoogle Scholar
  28. 28.
    Grutta VL, Sabatino M. Substantia nigra-mediated anticonvulsant action: a possible role of a dopaminergic component. Brain Res 1990; 515: 87–93.PubMedCrossRefGoogle Scholar
  29. 29.
    Sabatino M, Gravante G, Ferraro G et al. Striatonigral suppression of focal epilepsy. Neurosci Lett 1989; 98: 285–290.PubMedCrossRefGoogle Scholar
  30. 30.
    Sabatino M, Ferraro G, Vella N et al. Nigral influence on focal epilepsy. Neurophysiol Clin 1990; 20: 189–201.PubMedCrossRefGoogle Scholar
  31. 31.
    Velisek L, Veliskova J, Moshe SL. Electrical stimulation of substantia nigra pars reticulata is anti-convulsant in adult and young male rats. Exp Neurol 2002; 173: 145–152.PubMedCrossRefGoogle Scholar
  32. 32.
    Bressand K, Dematteis M, Gao DM et al. Superior colliculus firing changes after lesion or electrical stimulation of the subthalamic nucleus in the rat. Brain Res 2002; 943: 93–100.PubMedCrossRefGoogle Scholar
  33. 33.
    Deransart C, Le-Pham BT, Hirsch E et al. Inhibition of the substantia nigra suppresses absences and clonic seizures in audiogenic rats, but not tonic seizures: evidence for seizure specificity of the nigral control. Neuroscience 2001; 105: 203–211.PubMedCrossRefGoogle Scholar
  34. 34.
    DiChiarra G, Poceddu ML, Morelli M et al. Evidence for a GABAergic projection from the substantia nigra to the ventromedial thalamus and to the superior colliculus of the rat. Brain Res 1979; 272: 368–372.Google Scholar
  35. 35.
    Garant DS, Gale K. Substantia nigra-mediated anticonvulsant actions: role of nigral output pathways. Exp Neurol 1987; 97: 143–159.PubMedCrossRefGoogle Scholar
  36. 36.
    Chevlier G, Thierry AM, Shibazaki T et al. Evidence for a GABAergic inhibitory nigrotectal pathway in the rat. Neurosci Lett 1981; 21: 67–70.CrossRefGoogle Scholar
  37. 37.
    Kita H, Kitai ST. Efferent projections of the subthalamic nucleus in the rat: light and electron microscope analysis with the PHA-L method. J Comp Neurol 1987; 260: 435–452.PubMedCrossRefGoogle Scholar
  38. 38.
    Dybdal D, Gale K. Postural and anticonvulsant effects of inhibition of the rat subthalamic nucleus. J Neurosci 2000; 20: 6728–6733.PubMedGoogle Scholar
  39. 39.
    Sullivan HC, Osorio I. Aggravation of penicillin-induced epilepsy in rats with locus ceruleus lesions. Epilepsia 1991; 32: 591–596.PubMedCrossRefGoogle Scholar
  40. 40.
    Corcoran ME. Characteristics of accelerated kindling after depletion of noradrenaline in the rat. Neuropharmacology 1988; 27: 1081–1084.PubMedCrossRefGoogle Scholar
  41. 41.
    Shouse M, Langer J, Bier M et al. The alpha 2-adrenoreceptor agonist clonidine suppresses seizures, whereas the alpha 2-adrenoreceptor antagonist idazoxan promotes seizures in amygdala-kindled kittens: a comparison of amygdala and pontine microinfusion effects. Epilepsia 1996; 37: 709–717.PubMedCrossRefGoogle Scholar
  42. 42.
    Jobe PC, Dailey JW, Reigel CE. Noradrenergic and serotonergic determinants of seizure susceptibility and severity in genetically epilepsy-prone rats. Life Sci 1986; 39: 775–782.PubMedCrossRefGoogle Scholar
  43. 43.
    Szot P, Weinshenker D, White SS et al. Norepinephrine-deficient mice have increased susceptibility to seizure-inducing stimuli. J Neurosci 1999; 19: 10985–10992.PubMedGoogle Scholar
  44. 44.
    Szot P, Weinshenker D, Rho JM et al. Norepinephrine is required for the anticonvulsant effect of the ketogenic diet. Brain Res Dev Brain Res 2001; 129: 211–214.PubMedCrossRefGoogle Scholar
  45. 45.
    Sramka M, Chkhenkeli SA. Clinical experience in intraoperative determination of brain inhibitory structures and application of implanted neurostimulators in epilepsy. Stereotact Funct Neurosurg 1990; 54–55: 56–59.Google Scholar
  46. 46.
    Chkhenkeli SA, Chkhenkeli IS Effects of therapeutic stimulation of nucleus caudatus on epileptic electrical activity of brain in patients with intractable epilepsy. Stereotact Funct Neurosurg 1997; 69: 221–224.PubMedCrossRefGoogle Scholar
  47. 47.
    Velasco F, Velasco M, Jimenez F et al. Stimulation of the central median thalamic nucleus for epilepsy. Stereotact Funct Neurosurg 2001; 77: 228–232.PubMedCrossRefGoogle Scholar
  48. 48.
    Lesser RP, Kim SH, Beyderman DL et al. Brief bursts of pulse stimulation terminate afterdischarges caused by cortical stimulation. Neurology 1999; 53: 2073–2081.PubMedCrossRefGoogle Scholar
  49. 49.
    Yamamoto J, Ikeda A, Satow T et al. Low-frequency electric cortical stimulation has an inhibitory effect on epileptic focus in mesial temporal lobe epilepsy. Epilepsia 2002; 43: 491–495.PubMedCrossRefGoogle Scholar
  50. 50.
    Ullal GR, Ninchoji T, Uemura K. Low-frequency stimulation induces an increase in afterdischarge thresholds in hippocampal and amygdaloid kindling. Epilepsy Res 1989; 3: 232–235.PubMedCrossRefGoogle Scholar
  51. 51.
    McIntyre DC, Gilby K, Carrington CA. Effect of low-frequency stimulation on amygdala-kindled afterdischarge thresholds and seizure profile in fast and slow kindling rat strains. Epilepsia 2002; 43 (S7): 12.Google Scholar
  52. 52.
    Gaito J. The effect of variable duration one hertz interference on kindling. Can J Neurol Sci 1980; 7: 59–64.PubMedGoogle Scholar
  53. 53.
    Gaito J, Nobrega JN, Gaito ST. Interference effect of 3 Hz brain stimulation on kindling behavior induced by 60 Hz stimulation. Epilepsia 1980; 21: 73–84.PubMedCrossRefGoogle Scholar
  54. 54.
    Velisek L, Veliskova J, Stanton PK. Low-frequency stimulation of the kindling focus delays basolateral amygdala kindling in immature rats. Neurosci Lett 2002; 326: 61–63.PubMedCrossRefGoogle Scholar
  55. 55.
    Goodman JH, Berger RE, Scharfman HE et al. Low-frequency sine wave stimulation decreases seizure frequency in amygdala-kindled rats. Epilepsia 2002; 43 (S7): 10.Google Scholar
  56. 56.
    Durand DM, Warren EN. Desynchronization of epileptiform activity by extracellular current pulses in rat hippocampal slices. J Physiol 1994; 480: 527–537.PubMedGoogle Scholar
  57. 57.
    Warren RJ, Durand DM. Effects of applied currents on spontaneous epileptiform activity induced by low calcium in the rat hippocampus. Brain Res 1998; 806: 186–195.PubMedCrossRefGoogle Scholar
  58. 58.
    Jerger K, Schiff SJ. Periodic pacing an in vitro epileptic focus. J Neurophysiol 1995; 73:876–879. 59 Gluckman BJ, Neel EJ, Netoff TI et al. Electric field suppression of epileptiform activity in hippocampal slices. J Neurophysiol 1996; 76: 4202–4205.Google Scholar
  59. 60.
    Gluckman BJ, Nguyen H, Weinstein SL et al. Adaptive electric field control of epileptic seizures. J Neurosci 2001; 21: 590–600.PubMedGoogle Scholar
  60. 61.
    Ghai RS, Bikson M, Durand DM. Effects of applied electric fields on low-calcium epileptiform activity in the CAl region of rat hippocampal slices. J Neurophysiol 2000; 84: 274–280.PubMedGoogle Scholar
  61. 62.
    Bikson M, Lian J, Hahn PJ et al. Suppression of epileptiform activity by high frequency sinusoidal fields in rat hippocampal slices. J Physiol 2001; 531: 181–191.PubMedCrossRefGoogle Scholar
  62. 63.
    Barbarosie M, Avoli M. CA3-driven hippocampal-entorhinal loop controls rather than sustains in vitro limbic seizures. J Neurosci 1997; 17: 9308–9314.PubMedGoogle Scholar
  63. 64.
    Kano T, D’Antuono M, d Guzman P et al. Low-frequency stimulation of the amygdala inhibits ictogenesis in the perirhinal cortex. Epilepsia 2002; 43 (S7): 129.Google Scholar
  64. 65.
    Benazzouz A, Hallet M. Mechanism of action of deep brain stimulation. Neurology 2000; 55 (12 Suppl 6): S13–16.PubMedGoogle Scholar
  65. 66.
    Durand DM, Bikson M. Suppression and control of epileptiform activity by electrical stimulation: a review. Proc IEEE 2001; 89: 1065–1082.CrossRefGoogle Scholar
  66. 67.
    Stock G, Strum V, Schmitt HP et al. The influence of chronic deep brain stimulation on excitability and morphology of the stimulated tissue. Acta Neurochir (Wien) 1979; 47: 123–129.CrossRefGoogle Scholar
  67. 68.
    Haberler C, Alesch F, Mazal PR et al. No tissue damage by chronic deep brain stimulation in Parkinson’s disease. Ann Neurol 2000; 48: 372–376.PubMedCrossRefGoogle Scholar
  68. 69.
    Henderson JM, O’Sullivan DJ, Pell M et al. Lesion of thalamic centromedian-parafascicular complex after chronic deep brain stimulation. Neurology 2001; 56: 1576–1579.PubMedCrossRefGoogle Scholar
  69. 70.
    Saint-Cyr JA, Trepanier LL, Kumar R et al. Neuropsychological consequences of chronic bilateral stimulation of the subthalamic nucleus in Parkinson’s disease. Brain 2000; 123: 2091–2108.PubMedCrossRefGoogle Scholar
  70. 71.
    Dujardin K, Defebvre L, Krystkowiak P et al. Influence of chronic bilateral stimulation of the subthalamic nucleus on cognitive function in Parkinson’s disease. J Neurol 2001; 248: 603–611.PubMedCrossRefGoogle Scholar
  71. 72.
    Iasemidis LD, Sackellares JC, Zaveri HP et al. Phase space topography and the Lyapunov exponent of electrocorticograms in partial seizures. Brain Topogr 1990; 2: 187–201.PubMedCrossRefGoogle Scholar
  72. 73.
    Martinerie J, Adam C, Quyen MLV et al. Epileptic seizures can be anticipated by nonlinear analysis. Nat Med 1998; 4: 1173–1176.PubMedCrossRefGoogle Scholar
  73. 74.
    Lehnertz K, Elger C. Can epileptic seizures be predicted? Evidence from nonlinear time series analysis of brain electrical activity. Phys Rev Lett 1998; 80: 5019–5022.CrossRefGoogle Scholar
  74. 75.
    Osorio I, Frei M, Wilkinson S. Real-time automated detection and quantitative analysis of seizure and short-term prediction of clinical onset. Epilepsia 1998; 39: 615–627.PubMedCrossRefGoogle Scholar
  75. 76.
    Jerger KK, Netoff TI, Francis JT et al. Early seizure detection. J Clin Neurophysiol 2001; 18: 259–268.PubMedCrossRefGoogle Scholar
  76. 77.
    Sperling M, O’Conner M. Auras and subclinical seizures: characteristics and prognostic significance. Ann Neurol 1990; 28: 320–328.PubMedCrossRefGoogle Scholar
  77. 78.
    Bergey GK, Britton JW, Cascino GD et al. Implementation of an external responsive neurostimulator system (eRNS) in patients with intractable epilepsy undergoing intracranial seizure monitoring. Epilepsia 2002; 43 (S7): 191.Google Scholar

Copyright information

© Springer Science+Business Media New York 2004

Authors and Affiliations

  • Jeffrey H. Goodman

There are no affiliations available

Personalised recommendations